ABSTRACT BACKGROUND: Patients with multiple chronic conditions (MCC) are the largest consumers of healthcare in the US. Randomized controlled trials (RCT) of clinical effectiveness have not sufficiently studied these patients, while observational studies inherently produce biased estimates of clinical effectiveness. There are substantial disparities in health and healthcare for persons with MCC, particularly those with combinations of diabetes mellitus type II (DM), coronary artery disease (CAD) and chronic kidney disease (CKD). The effectiveness of statin therapy for preventing heart attacks and strokes remains unknown in populations with MCC. Furthermore, there is insufficient research done on how to best utilize existing data to study MCC in order to obtain answers that can assist these patients and their clinicians in healthcare decision-making. OBJECTIVE AND SPECIFIC AIM: The objective of this study is to help improve the utility of systematic review with meta-analysis as a method for studying the impact of MCC on clinical effectiveness. The specific aim of this project is to test the predictive value of systematic review with meta- analysis as a method for quantifying the impact of MCC on the clinical effectiveness of statin therapy for preventing heart attacks and strokes in patients with CAD, DM and CKD. METHODS: This study proposes to use systematic review with meta-analysis to identify, select and critically appraise relevant research studies, to synthesize the data from these studies in an effort to make recommendations for best practice, and to identify gaps in the literature that can lead to better-informed research for patients with MCC. A systematic review will be done to examine the impact of having MCC on the clinical effectiveness of statins for the prevention of heart attacks and strokes. AHRQ guidelines will be implemented to find, assess and synthesize the evidence from all studies, including both experimental and observational designs, which are relevant to the research question. Data from the included studies will be combined statistically to produce several meta-analyses. Meta-regression, subgroup, sensitivity and cumulative analyses will be performed to create quantitative measures of the impact of having different combinations of MCC on the effectiveness of statin therapy. PROJECTED OUTCOMES: The primary outcome of this project will be to determine how well systematic review with meta-analysis can help quantify the impact of having MCC on clinical effectiveness. A secondary outcome will be the quantification of this impact for the effectiveness of statin therapy, which represents one of the most widely prescribed treatments in the US. This study's recommendations will guide researchers on how to utilize systematic review with meta-analysis to analyze existing data on patients with other MCC. This will help reduce the need to conduct additional expensive and large experimental or observational studies, thereby rapidly improving clinical decision-making and speeding up the implementation of evidence into practice for these populations with special care needs.